P719: RANDOMIZED PHASE 1-2 STUDY TO ASSESS SAFETY AND EFFICACY OF LOW-DOSE (LD) ORAL DECITABINE/CEDAZURIDINE (ASTX727) IN LOWER-RISK MYELODYSPLASTIC SYNDROMES (LR-MDS) PATIENTS: INTERIM SAFETY ANALYSIS
Authors: Guillermo Garcia-Manero, Kimo Bachishvili, Elizabeth A. Griffiths, Amer M. Zeidan, Elie Traer, Lalit Saini, Harshad Amin, Sanjay Mohan, Michael Lübbert, Lori Maness-Harris, James M Foran, Dominik Selleslag, Blanca Xicoy Cirici, Daniel Aaron Pollyea, David Sallman, Aref Al-Kali, Jesus Berdeja, Haifa Kathrin Al-Ali, Nancy Y Zhu, Patricia Font Lopez, Guillermo Sanz Santillana, Valeria Santini, Habte A. Yimer, Larry D Cripe, Victor Priego, Olatoyosi Odenike, Bert Heyrman, David Valcarcel, Pankit Vachhani, Yuri Sano, Beloo Mirakhur, Aram Oganesian, Harold Keer, Abdulraheem Yacoub
Journal: HemaSphere (2023)

Background: Cedazuridine (CED), a cytidine deaminase (CDA) inhibitor allows oral availability of decitabine (DEC) and 5 daily doses of the fixed-dose combination of 35 mg DEC/100 mg CED standard dose (SD) provides equivalent exposure to an IV DEC regimen of 20 mg/m2 days 1-5 (Garcia-Manero et al, 2020). Attenuated HMA regimens (e.g., 3 days of IV DEC) have shown activity in LR-MDS (Jabbour, et al. 2017). Aims: This Phase 1/2 study explores the optimal dosing schedule of Low Dose oral DEC/CED in patients with LR-MDS. Methods: A two-part Phase 1/2 study is being conducted in LR-MDS (IPSS low risk and lntermediate-1) subjects requiring treatment. Phase 1 explored 6 different 28-day regimens, ranging from 5-20 mg DEC with 100mg CED and treatment duration of 5-10 days (Figure 1). The primary endpoints were determination of the recommended Phase 2 dose (RP2D) based on dose-limiting toxicities (DLT) and safety. Secondary endpoints included clinical activity based on modified International Working Group (IWG) 2006 MDS response criteria, transfusion independence rate, leukemia-free survival (LFS), and overall survival (OS). In Phase 2, 81 LR-MDS were randomly assigned in a 1:1 ratio to receive the RP2D from Phase 1 or 35 mg DEC/ 100 mg CED (SD) for 3 days, a regimen based on 3-day IV decitabine dosing in the NCCN guidelines for treatment of LR-MDS. Efficacy and safety endpoints of the Phase 2 were the same as those of the Phase 1. Results: In Phase 1, 47 patients were treated with five different DEC/CED regimens. DLT associated with prolonged neutropenia was seen in proportion to the dose per cycle and the number of days of treatment. Based on the clinical efficacy and safety profile, 10mg DEC/100mg CED for 5 days was selected as the RP2D. The Hematologic Improvement (HI) % for all dosing schedules was 30% (14/47), and the RBC transfusion-independent % over 8 weeks was 33% (7/21). Of the 47 patients treated, 23 (47%) had an event of death at the data cutoff, with a median OS of 31 months (95% Cl: 19, NE); the median LFS was 23 months (95% Cl: 14, 32). In Phase 2, IPSS INT-1 risk was 73% and 65% in the LD and SD arms, respectively. 48% were previously treated for MDS (21% and 26% were treated with ESA or luspatercept, respectively). At baseline, RBC and platelet transfusion dependence was 46% and 14%, respectively. At the data cutoff, 80 subjects had received a median of 4.5 cycles of treatment, and approximately 10 patients had discontinued treatment to receive bone marrowbone marrow transplant. In the pharmacokinetic analysis, the total cycle Area Under Curve (AUC) for decitabine in the LD 5-day was about half of the SD 3-day exposure and 1/4 of the SD 5-day exposure. Reported adverse event terms were similar to those reported for SD 5-day, with the most common grade ≥ 3 treatment-emergent adverse events (TEAEs) being neutropenia (19%), anemia (20%), and febrile neutropenia (6%). Average neutrophil counts by cycle 8 in subjects receiving LD 5-day regimen were slightly higher compared to subjects receiving SD 3-day dosing (Figure 2A), while changes in platelet count were similar in both arms (Figure 2B). Of the 8 all-cause deaths at data cutoff, only 2 and 1 were within 60 and 30 days, respectively, in the SD group. Summary/Conclusion: This Phase 1/2 study shows that a LD 5-day treatment regimen is tolerable and safe with less neutropenia, suggesting that it may be an optimal regimen for LR-MDS provided that longer term efficacy results prove to be comparable to the SD 3-day regimen.Keywords: MDS, Phase I/II, Oral